This proposal addresses the role of insulin resistance as a factor in the abnormal protein metabolism of chronic renal failure. Using a well-characterized muscle perfusion system, I will study uremic and sham-operated rats to determine dose response curves and degradation rates. Uremic animals will be studied during perfusion with both physiologic and pharmacologic concentrations of insulin. Individual rates of skeletal muscle protein synthesis, total hemicorpus protein and myofibrillar protein degradation will be determined in both fed and fasted animals. The site of insulin resistance in uremia will be determined by examination of the known steps within the pathways of protein synthesis and degradation. The role of leucine, another regulator of protein turnover whose site of action cannot be distinguished from that of insulin, will also be examined. The cause of the insulin resistance, the time course of its development, and the possible importance of circulating serum factors will be assessed in independent studies using, where appropriate, "uremic" perfusate and acutely versus chronically uremic animals. Pair-feeding studies will be performed to assess the role of undernutrition as opposed to uremia per se. In a chronically hyperinsulinemic rat model, I will examine the possibility that weight gain and muscle protein anabolism can be improved in uremia with exogenous insulin supplementation. Both in vivo and in vitro studies will compare protein turnover in uremic and in sham-operated control animals not receiving insulin supplementation. These studies have a direct bearing upon the abnormal protein metabolism, diminished weight gain and decreased muscle mass seen in patients, particularly children, with chronic renal insufficiency. A better understanding of these abnormalities could lead to improvements in the care of these individuals as well as a better understanding of the regulation of protein turnover under diverse physiologic conditions.